Prostate cancer (PCa) is a major health issue in the veteran's population. Initially, PCa presents as an androgen-sensitive tumor and responds to androgen ablation as the first line of therapy which results in regression of the cancer. However, the cancer frequently re-emerges and is no longer responsive to manipulation of androgen levels, even though the androgen receptor may be present in these cells. This form of the disease is termed castration resistant PCa (CRPC) and is generally fatal. Thus, the need for devising novel therapeutic approaches remains critical. Over the years, we have been focused on a serine/threonine protein kinase signal called CK2 for its involvement in the prostate pathobiology. Our discovery that CK2 not only promotes cell proliferation but also suppresses apoptosis has provided an important link of this signal to the cancer cell phenotype since cancer cells invariably demonstrate dysregulation of cell growth and cell death. In fact, suppression of apoptosis is a particularly defining feature of PCa. Importantly, the CK2 signal in PCa is equally functional in both phenotypes of PCa; specifically, those that are androgen-sensitive or -insensitive. This laboratory is the first to have proposed CK2 as an important target for PCa therapy prompted by the observations that molecular downregulation of CK2 or its inhibition by small molecule inhibitors results in cell death in PCa cells. In this VA Merit Review proposal, we aim to continue our studies on targeting CK2 for PCa therapy. Our working hypothesis is that dysregulation of CK2 is a key feature of the oncogenic phenotype, impacting apoptosis, cell growth, and survival; accordingly, its molecular downregulation specifically targeted in cancer cells should induce extensive cell death in vivo potentially resulting in eradication of primary and metastatic prostatic tumors. The focus of this submission is on the utilization of siRNA-based targeting of both the alpha and alpha` catalytic subunits of CK2. A novel aspect of our therapeutic strategy is that we have focused on devising delivery of therapeutic agents to downregulate CK2 only in cancer cells while sparing the normal cells. This selective delivery of the therapeutic agent is advantageous because the CK2 signal is ubiquitously present and essential in all cells. Our novel approach for drug delivery has a strong potential of directed delivery of the CK2-specific siRNA to the cancer cells in both primary and metastatic sites in animal models. We have made significant progress along these lines, and we are poised to move forward towards developing this novel therapeutic approach for PCa. We hope that this innovative preclinical study will be judged meritorious for continued investigation as this type of therapy may achieve disease eradication rather than simply resulting in disease stabilization. Our long term goal is to take this mode of therapy to the level of translation in PC patients.